The present technology generally relates to biologically active novel cannabinergic compounds. In particular, the present technology is related to novel cannabinergic nitrate esters and related analogs.
Marijuana (Cannabis sativa) and derivatives have been used for medicinal and recreational purposes. The major active constituent extracted from Cannabis sativa is the classical cannabinoid Δ9-Tetrahydrocannabinol (Δ9-THC). The effects of such cannabinoids are due to an interaction with specific high-affinity receptors. Subsequently, these discrete mammalian cannabinoid receptors, namely, CB1 and CB2, whose activation by Δ9-THC elicited psychotropic effects, were cloned. Studies revealed that in humans, CB1 and CB2 share≈44% sequence homology. The CB1 receptor subtype is localized primarily in the central nervous system (CNS), reflecting its prevalence as the most abundant GPCR in brain. CB1 receptors are distributed among the cortex, cerebellum, hippocampus, and basal ganglia, brain regions that control motor, cognitive, emotional, and sensory functions. Hence, central CB1 receptor activation mediates most cannabinoid psychotropic and behavioral effects. The CB1 receptor is also present in high density in the brainstem, hypothalamus, and pituitary gland, loci influencing pain perception; hormonal activity; thermoregulation; and cardiovascular, gastrointestinal, and respiratory physiology. CB1 receptors at peripheral sites (e.g., adipocytes, liver, uterus) help regulate such basic physiological processes as energy balance and reproduction. Although detectable at exceedingly low levels in brain, CB2 receptors are expressed mainly by immune and hematopoietic cells, osteoclasts, and osteoblasts and mediate immune responses, inflammation, inflammatory and neuropathic pain, and bone remodeling.
Virtually all cannabinoid-related medications thus far are related to Cannabis Sativa, most of which act as mixed agonists at both CB1 and CB2 receptors. Δ9-THC (dronabinol, Marinol®) and its synthetic analog, nabilone (Cesamet®) are used as anti-nausea and anti-emetic medications for chemotherapy patients. Nabilone is also approved as an appetite stimulant to treat acquired immune deficiency syndrome-related cachexia. Sativex®, a standardized Cannabis extract containing an approximately equal mixture of the two phytocannabinoids (Δ9-THC and cannabidiol) formulated as a sublingual spray, was initially used for alleviation of neuropathic pain in multiple sclerosis patients and subsequently approved for cancer pain relief.
Rimonabant (SRI 41716A) (Sanofi-Aventis) is a potent CB1-antagonist and its ability to suppress food intake and lower body mass has been demonstrated in humans. Rimonabant's efficacy as a weight-loss agent appeared to involve central, as well as peripheral, mechanisms mediated by the CB1 receptor. As with obesity, studies in appropriate models have shown that CB1-compounds including Rimonabant can decrease the rewarding and psychological/behavioral effects of nicotine, alcohol, and other abused drugs including cannabis, opioids, cocaine, heroin, morphine, and methamphetamine. De novo synthetic and high-throughput screening approaches have generated several novel CB1-receptor compounds more structurally distinct from Rimonabant, many of which have been tested in humans (ex. Taranabant, Surinabant, Otenabant, Ibipinabant and Drinabant).
Some of these compounds were radiolabeled and used as molecular probes and in whole body dosimetry studies as well.